1534 Chem. Res. Toxicol., Vol. 11, No. 12, 1998
Hainzl et al.
not alter the poisoning signs or mortality from fipronil
treatment at the LD50 dose.
nism and identity of the further metabolites are not
defined. In mice, the metabolism is slow for the de-
sulfinyl and sulfone derivatives relative to that for
fipronil (11).
Discu ssion
The toxicological properties of fipronil depend on the
parent compound, the sulfone metabolite, and the de-
sulfinyl photoproduct; i.e., each compound is a bioactive
component of fipronil-derived residues. The selective
toxicity of fipronil is due in part to the higher potency of
the parent compound at the insect than the mammalian
GABA receptor but is also dependent on the relative rates
of conversion to the more persistent and less selective
sulfone metabolite and desulfinyl photoproduct.
Fipronil is similar to R-endosulfan and lindane in its
high potency at the Drosophila and Musca GABA recep-
tors and in the cross resistance conferred by a low-affinity
target site. Much of the knowledge on receptor specificity
is derived from binding studies with [3H]EBOB. The
Musca and Drosophila GABA receptors are 70-fold more
sensitive than the vertebrate receptors to the three
fipronil derivatives and two PCCAs, on an overall basis,
suggesting that a fundamental target site difference is a
major factor in selective toxicity. More specifically, the
selectivity ratio relative to the human GABA receptor
(IC50 human/IC50 insect) is 135 for fipronil, 78 for lindane,
17 for the sulfone, 16 for the desulfinyl derivative, and
2.2 for R-endosulfan.
Fipronil sulfone is formed quickly from fipronil in
biological systems and plays a major role in its toxicology.
The sulfone, relative to fipronil, is more persistent, more
potent in vitro at the vertebrate GABA receptor (6-fold
overall in this study), and usually but not always more
toxic, i.e., with freshwater invertebrates, freshwater fish,
waterfowl, and upland game birds (19) but not mice (this
study). The PB antagonism of fipronil toxicity in German
cockroaches indicates that conversion to the sulfone is
an activation process (8).
Fipronil itself is a toxicant for mammals and an
insecticide even without oxidation to the sulfone. In
mice, the conversion of fipronil to the sulfone can be
completely blocked with PB (or NBI) for at least 2 h
without changing the poisoning signs or mortality from
fipronil treatment. However, the concentration of fipronil
in the brain does not correlate with the mortality or
poisoning signs since at an LD50 the mice that die at 6
min have 19 ppm fipronil in the brain and those that live
for 20 min have 32 ppm. The Musca GABA receptor is
more sensitive to fipronil than the sulfone, and PB
strongly synergizes the toxicity of fipronil (11), preventing
its oxidation to the sulfone and minimizing detoxification
of both fipronil and the sulfone.
Fipronil, fipronil sulfone, desulfinyl fipronil, and R-en-
dosulfan at their LD50 and higher doses inhibit [3H]EBOB
binding in brain on the basis of ex vivo assays in mice
(this study) in agreement with an earlier investigation
with many PCCAs using [35S]-tert-butylbicyclophos-
phorothionate as the radioligand (24). However, there
is one exception to this relationship since fipronil at a
concentration 2 and 4 times the LD50 can be lethal
without detectable inhibition of [3H]EBOB binding in
brain, possibly due to its lower affinity leading to dis-
sociation during the ex vivo assay. No explanation is
currently available for the greater inhibition level ob-
served for fipronil at the LD50 than at 2 or 4 times this
dose.
Ack n ow led gm en t. This project was supported by
Grant P01 ES00049 from the National Institute of
Environmental Health Sciences (NIEHS), NIH, and its
contents are solely the responsibility of the authors and
do not necessarily represent the official views of the
NIEHS, NIH. We thank our laboratory colleagues Gary
Quistad for advice and Charlemagne Lacza for perform-
ing the housefly treatments.
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